Medicine and Health Sciences Commons^™

Mitochondrial Unfolded Protein Response Regulator Atf5 In Mitochondrial Targeted Therapies In Aml, Ran Zhao

Dissertations & Theses (Open Access)

Mitochondrial unfolded protein response (UPR^mt) is an adaptive transcriptional response induced by damaged proteins accumulated in mitochondria. UPR^mt signaling involves induction of mitochondrial specific chaperones and proteases such as HSP60, LonP1 and ClpP, aiding in the restoration of mitochondrial protein pool homeostasis. However, the cell-protective roles of UPR^mt in the context of mitochondrial stress-induced cell death in AML has not been well explored. We demonstrate that AML cells are susceptible to mitochondrial targeted agents such as ONC201, an agonist of the mitochondrial protease ClpP, and gamitrinib, an inhibitor of mitochondrial chaperone TRAP1, however, these agents also …

Vascular Disease Pathogenesis In Smooth Muscle Dysfunction Syndrome And Majewski Osteodysplastic Primordial Dwarfism Type Ii, Jamie Wright

Dissertations & Theses (Open Access)

Vascular diseases are a leading cause of morbidity and mortality world-wide. Understanding their pathogenesis is crucial to better diagnosis and management of these life-threatening conditions. Through the study of rare mutations that lead to early onset and severe vascular diseases, we can elucidate underlying mechanisms for vascular disease pathogenesis and develop better treatments to prevent and manage more common causes of vascular diseases. In this study we look at two rare diseases that lead to severe vascular phenotypes, Smooth Muscle Dysfunction Syndrome (SMDS) and Majewski Osteodysplastic Primordial Dwarfism Type II (MOPDII). SMDS is a rare condition due to pathogenic variants …

The Role Of Ifitm3 In The Immune Response Of Brca-Deficient High Grade Serous Ovarian Carcinoma, Han Cun

Dissertations & Theses (Open Access)

Background: Prior studies showed that BRCA-deficient high grade serous ovarian carcinoma (HGSOC) had increased tumor infiltrating lymphocytes (TILs) compared to BRCA-wildtype (WT). To better understand the underlying immune mechanism in these tumors, a preliminary transcriptome analysis was performed on a set of microdissected HGSOC tumor specimens with BRCA1-mutation, BRCA2-mutation, or WT. This demonstrated an upregulation of IFITM3, an essential gene in modulating immune function. Based on these findings, we hypothesized that BRCA-deficient HGSOC have increased DNA damage leading to upregulation of IFITM3 and subsequent increase in antigen presentation and T-cell activation.

Methods: Following IRB approval, preliminary transcriptome analysis was performed …